INTRODUCTION TO AMYOTROPIC LATERAL SCLEROSIS
During the summer of 2011, I read the novel, Tuesday’s with Morrie, by Mitch Albom. The novel is about the life of retired sociology professor, Morrie Schwartz and his battle with the motor neuron disease, Amyotrophic lateral sclerosis (ALS). The novel really sparked my interest in this devastating disease and I had the desire to learn more about the symptoms, cause, and treatment of ALS.
Amyotrophic lateral sclerosis is also known as Lou Gehrig's disease after New York Yankee first baseman, Lou Gehrig, who was diagnosed with the disease in 1939. Affecting about 3 in every 100,000 people, ALS is a terrifying chronic, fatal neurodegenerative disease that leaves the individuals mind intact, while causing total paralysis of the body. Essentially, people with the disease lose all ability to move, but their cognition remains the same, so they are trapped within their own body. “Amyotrophic” refers to the atrophy, weakness, and fasciculation that signify disease of the lower motor neurons. “Lateral sclerosis” refers to the hardness that occurs on the lateral columns of the spinal cord in individuals with ALS (Festoff, 2001).
Although there is no specific diagnostic test, the clinical diagnosis is correct in more than ninety-five percent of cases. However, with the lack of an actual test it can sometimes be difficult to distinguish ALS from other motor neuron diseases such as Kennedy’s disease and X-linked spinobulbar muscular atrophy (Rowland, 2011).
The disease progression and symptom emergence varies from person to person, however, eventually most patients are unable to stand, walk, get out of bed, or use their arms and legs. People with ALS lose their ability to chew and swallow, making them unable to eat easily and increasing the likelihood of choking or aspiration of food and liquids. Pneumonia and the ability to maintain a healthy body weight become life threatening problems. Respiratory problems arise when the intercostal muscles of the ribs cage become weak and adequate diaphragm contraction is prohibited. Without diaphragm contraction, it is impossible to inhale the capability to breathe is lost. Usually there is no loss in the individual’s ability to see, taste, hear, feel, or blink. Bladder and bowel control is typically preserved also, however with the inability to walk and move, most people require catheters for excretion. Throughout the entire progression, the individual does not lose cognitive function and are aware of their condition, which often results in anxiety and depression. The prognosis of the disease is grim and individuals usually only live for three to five years after they are diagnosed with ALS (Festoff, 2001).
Although the origin of ALS is still not completely understood, scientists and physicians do have several theories on what may cause the disease. Heritable diseases are the only motor neuron diseases whose causes are known, with five to ten percent of ALS cases being familial, the rest are sporadic. In twenty percent of familial ALS, the there are mutations on the gene that make the superoxide dismutase (SOD1) enzyme. SOD1 is an antioxidant that protects the body from damage from the superoxide, a free radical made by the mitochondria and when they accumulate, can damage mitochondrial and nuclear DNA as well as proteins (Deng, 1993).
There are also several environmental causes that have links to ALS. First, the exposure to heavy metals may contribute to its progression. Lead intoxication has been attributed to cases of both upper and lower neuron syndromes; however, there have been no convincing reports of lead-induced motor neuron diseases in the last thirty years.
Viral infection is a second possible cause of sporadic ALS. Enterovirus RNA was detected in the spinal cords of patients with ALS, however the role of enteroviruses, including the polio virus have not yet been established, making it difficult link the cause of ALS to the virus. Motor neuron disease has also been reported in individuals infected with the human immunodeficiency virus (HIV) or in human T-cell lymphotropic virus type I, but the existence has been so low that it cannot prove that retroviral infection causes motor neuron disease (Ido, 2011)
Besides familial links, environmental factors, and viruses, scientists have some additional theories on the cause of ALS. Autoimmunity may play a role in the disease’s pathogenesis. Activated microglia and T cells have been present in the spinal cords of patients with ALS who have IgG antibodies against motor neurons. In patients with sporadic ALS, antibodies against voltage-gated calcium channels may cause interference with the intercellular calcium regulation, which may lead to the degradation of motor neurons. Immunotherapy has not been effective for patients with ALS, making the idea of an autoimmune cause of ALS controversial because if the cause of ALS is autoimmunity, then immunotherapy should work as a cure (Rowland, 2001).
Although the exact molecular pathways are that cause motor neuron death in ALS patients is still unknown, there are several possible primary mechanisms including the toxic effects of mutated SOD1, including abnormal protein aggregation, the disorganization of intermediate filaments, and glutamate-mediated excitotoxicity (Rowland, 2001).
Clinically, sporadic ALS and familial ALS are pathologically similar, suggesting they have a common cause. The SOD1mutation is only found in about two percent of patients with ALS, but the discovery of this mutation was extremely important because it was the first molecular link to the cause of the disease. In order to catalyze the conversion of toxic superoxide radicals to hydrogen peroxide and oxygen, SOD1 needs a copper atom at the active site to mediate catalysis. SOD1 also has pre-oxidant activities, including peroxidation, the generation of hydroxyl radicals and the nitration of tyrosine. Impairment of the antioxidant functions of associated with mutations of SOD1 could lead to the toxic accumulation of superoxide, resulting in a possible molecular mechanism of ALS (Deng, 1993).
A mutation in SOD1 could also alter the enzyme in a way that enhances its reactivity with abnormal substrates. For example, if the radical peroxynitrate is used as a substrate of SOD1, abnormal tyrosine nitration could damage proteins. In patients with ALS, free nitrotyrosine levels in the spinal cord are elevated (Deng, 1993).
Oxidative damage may occur when mutations in SOD1 impair the ability of the enzyme to bind to zinc. When deprived of zinc, SOD1 is less efficient at using superoxide, and the rate of tyrosine nitration increases. Mutations in SOD1 decrease the enzyme’s affinity for zinc, making the protein more likely to assume a toxic, zinc deficient state. Zinc-deficient SOD1 still requires copper at the active site even though its activity is irregular. Chelators (binding agents that suppress chemical activity by creating a ring shaped chemical compound called a chelate which contains a metal ion attached by coordinate bonds to at least two nonmetal ions) remove copper from zinc-deficient SOD1 but not from normal SOD1. The chelators protected cultured motor neurons from zinc-deficient SOD1, and eventually this discovery may be beneficial in finding a treatment for ALS (Deng, 1993).
Possible targets of the SOD1-induced toxicity described earlier include neurofilament proteins composed of heavy, medium, and light subunits. These subunits are important in determining the shape of cells and in axonal transport. Large-caliber, neurofilament –rich motor neurons are affected in individuals with ALS and the amount of neurofilaments may be important in selective neuronal vulnerability. In patients with ALS, neurofilaments accumulate in the cells and proximal axons of motor neurons, and with the accumulation, the neurofilaments become disorganized which could impede the axonal transport of molecules necessary for the maintenance of axons resulting in axonal strangulation and degeneration of motor neurons (Rowland, 2001).
This abnormal amount of neurofilaments may be a result of SOD1 mutation. In mice with SOD1 mutations, expression of the light subunit neurofilaments was eliminated, resulting in the overexpression of heavy subunits ameliorating motor neuron disease. However, this overexpression of heavy subunits has not yet been observed in humans, so it is unknown if the abnormal amounts of neurofilaments is the cause of ALS, or a byproduct of the disease (Rowland, 2001).
Calcium homeostasis and excitotoxicity is another molecular model that may explain the cause of ALS. There has been evidence that indicates ALS involves a derangement of intracellular free calcium. Cell death is triggered when abnormal calcium homeostasis activates a chain of several events. In both human ALS patients and mice with mutant SOD1, the resistance to the degeneration of certain motor neurons such as the oculomotor neurons, may be related to calcium-binding proteins protecting against the toxic effects of high intracellular calcium levels (Festoff, 2001).
When excitotoxic injury of neurons occurs, there is excessive entry of extracellular calcium through inappropriate activation of glutamate receptors. The main excitatory neurotransmitter in the central nervous system is glutamate. Glutamate works through two different types of receptors: the G protein-coupled receptor, which upon activation, leads to the release of intracellular calcium stores, and the glutamate-gated ion channels, which are characterized by their sensitivity to N-methyl-D-aspartic acid (NMDA) (Festoff, 2001).
The NMDA-receptor channel can be permeated by calcium, but the permeability of the non-NMDA0receptor channel is dependent upon the composition of the receptor. If the subunit GluR2 is present, the channel is impermeable to calcium, however if AMPA receptors, which lack GluR2, are present, the channel can be permeated by calcium. Motor neurons have selective vulnerability to AMPA. This vulnerability could be explained because GluR2 expression in motor neurons is lower than in other neurons, or by an editing impairment of GluR2 mRNA in patients with ALS. Either situation would lead to the expression of calcium-permeable AMPA receptors (Festoff, 2001)
Because increased level of glutamate is found in the cerebrospinal fluid of ALS patients, the possibility of glutamate excitotoxicity was suggested. High levels of glutamate could cause excitotoxicity, which would result in increased amounts of free calcium through the activation of calcium-permeable receptors and voltage-gated calcium channels. The increased glutamate level could also be from impaired glutamate transport in the central nervous system, however this theory is still not understood and more research must be done on humans (Festoff, 2001).
A last molecular mechanism for the explanation of ALS is apoptosis. There are many ALS triggers that could perturb cellular functions that are essential for the survival of motor neurons. Motor neurons probably die as a result of apoptosis in SOD1-mediated ALS. However, this idea is highly disputed. Caspase protease activation in response to Bcl-2 proteins must occur in order for apoptosis to occur. In mice with SOD1 mutations, the expression of Bcl-2 delayed the start of motor neuron disease and prolonged life. Interleukin-1β-converting enzyme (a caspase inhibitor) also slowed ALS progression. Although apoptosis is one of the later events motor neuron degeneration, it may be one of the causes of ALS (Rowland, 2001)
The glutamate antagonist drug, riluzole, is the only FDA approved medication for the treatment of ALS, and in two therapeutic trials, it prolonged life by three to six months. In one of the trials, it also slowed the loss of limb function, but only slightly. The success of the drug has been taken as evidence in support of the excitotoxic-glutamate theory of pathogenesis for ALS. Other glutamate antagonists have not proven to be beneficial though, and there are no other drugs that have been found to decrease the progression of the disease or increase lifespan (Festoff, 2001).
Since there are is no cure for ALS, efforts and treatments to make an ALS patient more comfortable and improve quality of life are taken. Mechanical ventilator support is a huge decision patients must face and they must make the decision to undergo a tracheostomy for long-term mechanical ventilation must be made. The need for a tracheostomy can be postponed, however, if the individual chooses to use a noninvasive positive pressure ventilation system commonly called BiPAP. BiPAP forces oxygen into the person’s lungs by the use of positive pressure. Very few patients opt to undergo a tracheostomy as it inhibits movement and the ability to communicate (Rowland, 2001).
Because ALS is such a terrifying and debilitating disease, most patients become severely depressed. Antidepressants are often prescribed to help boost the patient’s morale in their final years of life. Some people do not like to take antidepressants and often find psychological and spiritual help to be more effective methods to control depression (Festoff, 2001).
Amyotrophic lateral sclerosis is a horrifying, painful disease that is always fatal. Currently, there is only one medication used to prolong life by only a mere three to six months. An individual with ALS is completely aware that they are facing a terrible death where their mind will remain intact while their body quickly betrays them. More research on the cause of this neurodegenerative disease must be done before a treatment can be found and hopefully stop the progression of the disease before the individual becomes a prisoner in their own body and dies a dreadful death.